Is ACAN p.Pro541= (c.1623C>A) pathogenic?

ACAN p.Pro541= (c.1623C>A) is classified Benign in ACAN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-05-08). Common (popmax 89.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with osteochondritis dissecans.

What condition is associated with ACAN p.Pro541= (c.1623C>A)?

ACAN p.Pro541= (c.1623C>A) is associated with osteochondritis dissecans, spondyloepiphyseal dysplasia, Kimberley type, spondyloepimetaphyseal dysplasia, aggrecan type (ClinVar).

How is Osteochondritis dissecans inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

ACAN p.Pro541=

Q: How common is ACAN p.Pro541= (c.1623C>A) in the general population?

ACAN p.Pro541= (c.1623C>A) is common (popmax 89.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1623C>A · rs2272023 · VCV1188849

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 89.2%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

osteochondritis dissecans

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.8	GERP -3.8
Overall
CADD	0.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 89.2% African / African-American · 66,866/74,996 alleles

Filtering AF 88.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 88.4%

Overall 73.8% 1,190,048/1,613,524 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	89.2%	1
Middle Eastern	78.9%	1
Ashkenazi Jewishnot grpmax-eligible	76.2%	1
European (non-Finnish)	75.9%	1
Remaining individualsnot grpmax-eligible	73.6%	1
Amishnot grpmax-eligible	70.6%	1
Finnishnot grpmax-eligible	67.4%	1
South Asian	66.7%	1
Admixed American	53.8%	2
East Asian	40.3%	2

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ACAN
Protein: p.Pro541=
Coding: c.1623C>A
MANE Select: NM_001369268
dbSNP: rs2272023
Type: single nucleotide variant
Location: chr15:88847929 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 541: a disulfide bond; the link 3 domain; the 'g2-b' region

Full ACAN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

osteochondritis dissecans — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondyloepiphyseal dysplasia, Kimberley type spondyloepimetaphyseal dysplasia, aggrecan type

For Osteochondritis dissecans (Orphanet):

Inheritance: Not applicable
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ACAN c.1733-2A>G Likely pathogenic ★★ same condition
ACAN p.Arg675Ter Pathogenic/Likely pathogenic ★★ same condition
ACAN p.Asp2419Asn Likely pathogenic ★★ same condition
ACAN p.Tyr164Ter Pathogenic ★★ same condition
ACAN p.Ala171Val Uncertain significance ★★ ⚠ same condition
ACAN p.Arg2503Gln Uncertain significance ★★ ⚠ same condition
ACAN p.Arg2503Trp Uncertain significance ★★ ⚠ same condition
ACAN p.Arg2560Trp Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/acan-p-pro541 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown